Ligature device and method of use

ABSTRACT

The present invention is an apparatus and method for ligation. The ligation apparatus or band provides topical active agent(s) that alleviate pain during various ligature procedures. This invention also relates to a method that includes applying a loop or band around a body part for elastomeric ligation, whereby the band material supplies a topical active agent (s) to the body part to reduce the pain of ligation.

I. FIELD OF THE INVENTION

This invention relates to an apparatus and method for ligation. Theligation device incorporates and provides a topical active agent(s) thatalleviates pain during various ligature procedures.

This invention also relates to a method that includes applying aligation device around a body part for ligation, whereby the material ofthe device supplies a topical active agent(s) to the body part to reducethe pain of ligation. Preferred examples of ligation devices of theinvention include elastomeric loops or bands commonly used forcastration and docking by ligation in animals.

II. BACKGROUND OF THE INVENTION

Ligation with an elastic band, or “elastration”, is a bloodless methodof male castration and docking commonly used for livestock. Elastrationinvolves placing a tight elastic band, or elastrator, around the bodypart of an animal to reduce the blood flow to the part so that itwithers and falls off. To reduce the discomfort to the animal duringthis procedure, either the elastration band or the body part or both canbe coated with an anesthetic such as lidocaine prior to placement on theanimal. The secondary step of applying anesthetic during elastrationadds cost, inventory and labor to the procedure that could be avoided ifthe anesthetic could be incorporated into the elastration band itself.The topical agents that are applied during elastration provide onlytemporary pain relief that wears or washes off quickly and must bereapplied to provide prolonged pain relief during the entire elastrationperiod.

In other known procedures, lidocaine is injected into the animal bodypart. This injection typically provides only about three hours of painrelief, in contrast to the present invention which may provide painrelief for 21 days or longer.

Notwithstanding the usefulness of the above-described methods, a needstill exists for better methods of reducing the pain and stress to ananimal undergoing elastration.

III. SUMMARY OF THE INVENTION

This invention provides a device for use in ligation procedures, whereinthe device comprises at least one active agent or active agentcomposition for the treatment of pain. A preferred embodiment of theinvention is an elastomeric band or loop for elastration that containsone or more active agents to reduce the pain of elastration.

An advantage of the invention is the band dispenses a localizedanalgesic/anesthetic over time that provides extended duration painrelief for animals undergoing ligation or castration, or for any animalundergoing any procedure that would benefit from the application of alocal analgesic/anesthetic through a band.

The present invention discloses a method and apparatus for ligation thatavoids or alleviates the problems discussed above. The present inventionprovides a ligature band (with active agent(s)) for attachment to ananimal body or part thereof where the band or a part thereof releasesthe active agent(s). The release of the active agent reduces the painand or stress to the animal, and may also reduce the likelihood ofswelling and infection.

The purpose of this invention is to produce an elastration band thatcontains one or more agents that relieve pain, (e.g. anesthetics andanalgesics) so that both the band and the active agent(s) are appliedsimultaneously to the animal. An anesthetic such as lidocaine can beincorporated into the elastration band by several methods. The agent canbe coated onto the band, infused into the material of the band, orinserted into the center of a hollow elastration band.

With the following enabling description of the drawings, the apparatusshould become evident to a person of ordinary skill in the art.

IV. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an embodiment of the invention in which the ligationapparatus is a band and the apparatus includes a cinch pull.

FIG. 2 shows an embodiment of the invention wherein the ligationapparatus is a band or tube having two ends, in which the ends may befastened together; and wherein the loop may be tightened or closed witha constrictor.

FIG. 3 shows variously configured and shaped bands of the presentinvention, any of which can be infused with one or more active agents asdescribed herein.

FIG. 4 is a chart comparing scrotal temperatures above and below acontrol elastration band with scrotal temperatures above and below aLidocaine elastration band.

V. DETAILED DESCRIPTION OF THE INVENTION

The present invention is a ligation device that elutes or delivers oneor more active agents, wherein the device provides topical or local painrelief. In preferred embodiments of the invention, the device comprisesan elastomeric tube or band containing one or more active agents. Insome embodiments of the invention, the band itself elutes the activeagent(s). In preferred embodiments of the invention the ligation deviceis an elastration band.

Active agents, as used herein, refer to one or more analgesics; one ormore anesthetics; one or more antibiotics; one or more skin permeationor penetration enhancers; one or more anti-inflammatory agents; one ormore hormones; one or more chemical indicators, e.g., visual orperformance indicators; one or more vasoconstrictor agents; andcombinations thereof.

Band, as used herein, refers to a band, ring, tube, straw, conduit, orthe like. In some embodiments, the band is a length of tube or rubberhaving two ends; in these embodiments, the band may also include one ormore fasteners and/or one or more crimpers or clamps. In otherembodiments, the band is a closed loop. In preferred embodiments of theinvention, the band is elastomeric. The band of the present invention isdescribed in more detail below.

The present invention is also a method of making a ligature bandcomprising dissolving one or more active agent(s) or a compositioncomprising one or more active agents in a solvent or solventcomposition, then soaking or contacting the band in the solvent/activeagent composition. The band swells in the solvent and absorbs the activeagent(s), then the solvent is evaporated, trapping the agents in theband, and thereby providing an active agent-eluting band.

In preferred embodiments, the solvent formulation also contains anadditional skin permeation enhancer. In other embodiments, the methoduses a solvent formulation that contains one or more additional activeagents dissolved in the formulation.

Another embodiment of the present invention involves a band or tube of apredetermined length or diameter comprised of an elastomeric materialwherein the material comprises one or more active agents suitable forproviding a beneficial topical treatment for the animal.

A preferred embodiment of the invention comprises an elastomeric band,e.g., a band made from rubber, that is coated or infused with lidocaine.In a preferred embodiment, the band contains an analgesic/anesthetic anda skin permeation enhancer. In these embodiments of the invention, theband releases its active agent over time (i.e., controlled release ofactive agent(s)). As used herein, controlled release refers to therelease of active agent over time. This period may be 21 days or longerdepending on the active agent composition. Controlled release is atleast 1 day, preferably at least 5 days, and most preferably up to about15 days. In typical use, the band stays on until the body part fallsoff.

In accordance with the present invention, the apparatus or band elutesor delivers a sufficient amount of active agent to provide quick actiononset, as well as prolonged duration of the active agent activity. Oneskilled in the art will recognize that an effective amount, quickaction, onset, and duration are all characteristics that may vary orinteract in achieving a band having analgesic properties.

The present invention is treating an animal to prevent or mediate painby applying an agent-eluting band to an animal or body part in needthereof. Some embodiments of the invention include treating an animal toprevent or mediate pain and infection by applying a device of thepresent invention.

A band of the present invention may be placed on the animal by hand, ormay be placed on the animal using a device or applicator. In theembodiments in which the band is placed using an applicator, the bandand applicator may be configured and adapted to work together, as iswell known in the art.

Alternatively, the present invention may also involve a method oftreating an animal in pain comprising administering or applying aligation apparatus or an elastomeric material of the present invention.

The present invention also may involve an elastrator or ligation bandcomprising an elastomeric material comprising at least one active agentfor the topical treatment of pain.

The elastomeric band may comprise any material that is suitable ormedically appropriate for use as a ligation band as described herein.Typical elastomeric materials include but are not limited to rubber(natural, synthetic, or silicone) or thermoplastic elastomers, includingpolybutadiene, polyisoprene, polychloroprene, nitrile, SBS, SEBS, EPDMand polyurethane. The band may be solid, hollow, porous, or tubular(e.g., defining a lumen). In embodiments of the invention where the bandis tubular, the anesthetic may be infused into the material, containedwithin the lumen of the tube or both infused into the material andcontained within the lumen.

In other embodiments of the invention, the band includes a second bandor sleeve that elutes or delivers the active agent.

In embodiments of the invention that include a sleeve, the sleeve issolid, hollow, porous, or tubular (e.g., defining a lumen). In someembodiments, the sleeve may be a layer or coating.

Some embodiments of the invention also include one or more additionalactive agents that are capable of being transferred to the body partafter contact with the band. The additional active agent(s) include, butare not limited to, one or more of the following: a second analgesicagent, such as Meloxicam, an anesthetic agent, an anti-inflammatoryagent, antimicrobial agent, an antibiotic, a hormone or combinationsthereof.

A band of the present invention includes at least one active agent thatis capable of being transferred to the body part after contact with theband or sleeve. In preferred embodiments, the active agent is a localanesthetic or analgesic, or is a composition that includes a localanesthetic and/or analgesic. A suitable or exemplary anesthetic oranalgesic includes, but is not limited to one or more of the following:lidocaine or meloxicam.

A band of the present invention also includes a permeation enhancer. Asused herein, a permeation enhancer refers to a substance or chemicalthat increases or modulates absorption of an active agent by the skin ofthe animal. To enhance local anesthesia, chemicals that increase thepercutaneous penetration of the anesthetic are also incorporated intothe elastration band. Such permeation enhancers are known to the art oftransdermal drug delivery. For the example of an elastration bandcontaining lidocaine, useful permeation enhancers include but are notlimited to: fatty acids (e.g. palm oil); fatty acid esters (e.g.isopropyl myristate); poloxamers (e.g. poloxaline), triglycerides (e.g.,amine oxides, such as cocamine oxide), n-methyl pyrrolidone, povidone,terpineol, DMSO, and dimethylacetamide. Because of the hydrophobicnature of skin, the free base of lidocaine is used rather than a morepolar lidocaine salt to enhance skin penetration. The inventors believethat permeation enhancers are not typically used in elastrator bands.

One skilled in the art will recognize that the choice of permeationenhancer is tied to the particular analgesic or anesthetic being usedand may also be selected based on its ability to diffuse from theelastomeric band. Suitable permeation enhancers for lidocaine aredescribed in Mohammadi-Samani, et al.; Pak. J. Pharm. Sci., Vol. 23, pp83-88 (2010), incorporated herein by reference.

Some embodiments of the invention include one or more anti-inflammatoryagents. Anti-inflammatory agents include but are not limited toNon-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam,flunixin, ketoprofen, diclofenac, and ibuprofen. Steroidalanti-inflammatory agents include but are not limited to dexamethasone,flumethasone, prednisolone, prednisone, and immune selectiveanti-inflammatory derivatives (IMSAIDs). The inventors believe thatanti-inflammatory agents are not typically used in elastrator bands.

Some embodiments of the invention include one or more hormones. Hormonesinclude but are not limited to: cortisone, hydrocortisone, trenbolone,testosterone, and estradiol. The inventors believe that hormones are nottypically used in elastrator bands.

Some embodiments of the invention include vasoconstrictive agents suchas epinephrine, pseudoephedrine, phenylephrine, thromboxane andangiotensin. Vasoconstrictor agents for use in the invention are knownby those with skill in the art.

Some embodiments of the invention also include one or more chemicalindicators such as dyes, pigments, pH indicators or stains to furtherdifferentiate that the bands contain active agent(s). These chemicalindicators could also release with the active agents to provide visualevidence of active agent release to the area of application. In somecases, the chemical indicator may also be an active agent. Examplesinclude, but are not limited to the use of antimicrobial dyes such asgentian violet, which stains the area a blue-purple color and also actsas a topical antimicrobial agent that helps prevent infection at thesite of elastration. In other examples the chemical indicator includesthe use of pH indicators to identify alkaline pH, which is correlatedwith infection. Examples of other chemical indicators that could beincorporated into devices of this invention include, but are not limitedto, Nile Red, Oil Red, Sudan Red, Congo Red, cresol red, Coomassie Red,Coomassie Blue, methylene blue, Oil Blue, gentian violet, Azure blue,Malachite green, Eosin dyes, Rhodamine dyes, haematolxylin,phenolphthalein, resazurin, phenol red, methyl red, bromothymol blue,thymol blue, alizarin yellow, povidone iodine, and natural dyes such asindigo, turmeric, Catechu and Annatto extract.

The most preferred embodiment of the invention is an elastration bandinfused with or coated with an anesthetic and analgesic, and apermeation enhancer. The most preferred example is a band infused withlidocaine and isopropyl myristate (IPM).

The composition comprising at least one active agent may form a coatingon the band or may be infused into the band material. A coating mayinclude a powder, liquid, wax, hydrogel or other polymer.

Some embodiments of the invention may also include soaking the band insolvents, such as DMSO (dimethyl sulfoxide) or THF (tetrahydrofuran), toswell the band and cause absorption of the active agents and skinpermeation enhancer into the band.

Another method of incorporating anesthetic into elastration bandsapplies to the use of hollow elastration tubing to construct some largerelastration bands. Anesthetic formulations containing permeationenhancers and other agents including solvents can be incorporated intohollow elastration bands by injection of the solution into the hollowcenter of the band. A solvent that swells the polymer of the band can beincorporated into the formulation to provide migration of the anestheticand permeation enhancer through the walls of the band to the surface ofthe band to provide both fast-acting anesthetic and a reservoir ofanesthetic that releases over time. Alternatively, aqueous emulsions ofactive agents can be used in the center of the tube to prolong thediffusion of active agent. This method is best used in conjunction withcoating and infusion methods to provide additional agent(s) for moreprolonged release.

Another method of incorporating anesthetic into elastration bandsapplies to the use of a drug loaded sleeve that is positioned on theband in the area of greatest scrotal tissue contact on the tubularelastrator. The sleeve may be free floating, a partial polymer coatingor an adhesive sleeve, each containing anesthetic and permeationenhancers.

Another method of incorporating anesthetic into elastration bands is bycompounding the active ingredient into a polymeric material that can besubsequently molded into the devices of the invention using commonpractices known to the art. As examples, compounding can be achievedwith heat and shear, as for compounding into thermoplastic materials, orby mixing with reactive prepolymer components at room temperature, aswith silicone rubber, before being molded and cured into the devices ofthis invention. Typical molding methods include, but are not limited to,injection molding, compression molding, extrusion, reaction injectionmolding, casting, rotational molding, matrix molding, blow molding,laminating, transfer molding and other methods of thermoforming.

An invention as described herein may include one or more methods ofmaking the apparatus or band. An embodiment of the invention may includea method of making a hollow ligation apparatus comprising introducinginto the lumen of the apparatus a solution or emulsion of active agentscomprising one or more analgesics; one or more anesthetics; one or moreantimicrobial agents; one or more antibiotics; one or more skinpermeation or penetration enhancers; one or more anti-inflammatories;one or more hormones; one or more chemical indicators; one or morevasoconstrictor agents; and combinations thereof.

Another embodiment of the invention may include soaking or coating theapparatus in a solution of active agents comprising one or moreanalgesics; one or more anesthetics; one or more antimicrobial agents;one or more antibiotics; one or more skin permeation or penetrationenhancers; one or more anti-inflammatories; one or more hormones; one ormore chemical indicators; one or more vasoconstrictor agents; andcombinations thereof.

Another embodiment of the invention may include a method of making aligation apparatus comprising at least one active agent for the topicalcontrol of pain, said method comprising the compounding of activeagent(s) into thermoplastic elastomers followed by thermoforming.

Another embodiment of the invention may include a method of making aligation apparatus comprising at least one active agent for the topicalcontrol of pain, said method comprising the compounding of activeagent(s) into one or more of the unreacted part(s) of castable thermosetresins prior to mixing, casting and curing the resins. In preferredembodiments of the invention, the thermoset resin comprises silicone.

As noted above, a ligation apparatus may be formed or made from variousmaterials. In some embodiments of the invention, the ligation apparatusmay be a band; a tube; an elastomeric band or tube; a hollow band ortube; a polymer; a zip-tie; a rope; a rope made from natural material;and a rope made from synthetic material.

In one embodiment, different sized bands are provided in order toperform ligation on different body parts, sizes, types, ages, etc. ofanimals. A band may also be sized or configured for use with aparticular applicator and device. Various devices known in the artemploy an endless loop band. Although endless loop bands may accommodatevarious different size animals and parts, they may present a risk ofapplying excessive or inadequate tension. An exemplary band is shown inFIG. 1 . The illustrated embodiment shows band or tube 11, and alsoshows a convention cinch pull 12 with tab 13.

A band of the present invention may be adjustable or adjusted to fit thesize and/or shape of the subject animal. An exemplary ligation apparatusis shown in FIG. 2 . In FIG. 2 , the ligation apparatus 20 is a band ortube having first and second ends, 21 and 22 respectively. The band ortube may be formed into a loop using a fastener or crimp 23. In someembodiments of the invention, the apparatus size may be adjusted using aconstrictor 24 or the like.

The present invention further contemplates the use of different sizedbands. For example, a band is provided that is suitable for ligation ofsmall animals, such as infant calves or sheep (FIG. 3C). A band ofsimilar design is further provided for a medium sized animal, such as amore developed calf. This medium sized band is larger in initialcircumference and/or has a higher elastic force (FIG. 3B). Bands mayalso be provided for larger animals, such as grown bulls (FIG. 3A).These bands may be further color coded and/or labeled so as to readilyprovide information to a user and reduce the risk of using an improperlysized band, which could result in a failed ligation.

The invention also involves a method for decreasing or modulating painin animals undergoing a ligation or castration procedure.

Another aspect of the present invention involves a method for ligating abody part of an animal, preferably a tail or scrotum. In preferredembodiments of the invention, the band may be expanded over the bodypart and released. In some of these embodiments, no tool is required toattach the band to the body part. In other of these embodiments, theband is expanded with a tool before applying over a body part.

Another method involves manually passing a preformed endless loop ofligature material around the body part of the animal. The endless loopis then pulled using various means integral to a ligature tool (e.g.winding mechanisms, pulling mechanisms, etc.) to tighten the loop aroundthe animal's body part. Once the endless loop is sufficiently tightened,it is secured to maintain adequate pressure around the animal's scrotum.Preferably, the step of securing comprises deforming a grommet or othercrimping device around the endless loop, while the pulling of theendless loop is accomplished by winding the endless loop around awinding spool integrally attached to the ligature tool. To improve theefficiency and cost of the method, a winding tether and attached hookmay be utilized to reduce the overall length of ligature materialnecessary. After the grommet is deformed around the endless loop tosecure the portion of the loop surrounding the body part, the excessligature material above the grommet may be removed by cutting the partof the loop that is not around the body part with a sharp knife, razorblade or other suitable instrument. Alternatively, the band material canbe unwound or otherwise released from the tool, thus eliminating theneed to cut the band so as to release it from the tool.

In a preferred embodiment of the invention, the band is an elastomericmaterial infused with or coated with an anesthetic agent, and the hollowcenter of the band (if any) is optionally filled with a formulation thatincludes an anesthetic agent. Suitable anesthetics include but are notlimited to lidocaine.

Some embodiments of the invention also include two ends of thepredetermined length of the elastomeric material disposed substantiallyparallel to each other, and an anchor member or tang portion that issecured to the two ends of the elastomeric material of predeterminedlength, which is used by the ligature tool to tighten the loop aroundthe animal's body part. In such embodiments, a crimping band is alsoprovided, the crimping band being translatable along at least a portionof the length of a band in an un-crimped state. After the loop istightened around the body part, the band is crimped to hold the two endsof the loop in place and the excess material may be trimmed from theattached loop.

One skilled in the art will recognize that a band of the presentinvention may be incorporated into a system according to the invention.A system of the present invention may include, but is not limited to oneor more of the following: packaging, the band, a vial or the like ofanesthetic; and a vial or the like of permeation enhancer.

One skilled in the art will recognize that the invention as describedherein may be reconfigured into different combinations, elements, andprocesses that are included within the scope of the invention.

This invention is in the general field of methods and apparatus fornon-surgical removal of animal tails, horns, testicles, and the like. Itis further directed to the foregoing mentioned field wherein a resilientring of rubber, or the like, is formed, having is very small opening butbeing expandable to slip over the portion of the animal to benon-surgically removed and then released onto such member so as tocompletely cut-off the flow of blood from the main portion of the animalto the member, at the same time pulling the skin adjacent the animalinto a configuration such that the skin covers the area from which themember was removed. The invention is even further directed to thenon-surgical removal of tails from swine by expanding the ring in aunique triangular configuration by utilization of a unique ringexpanding tool and applying the ring around the tail of the swine andremoving the ring from the expanding tool.

VI. EXAMPLES

Method 1: Soaking Solution

An elastic band or tube made for elastration of animals is soaked in avolatile organic solvent solution that contains at least one anestheticor analgesic and one skin penetration enhancer. Both the anesthetic andthe skin penetration enhancer (the “agents”) are completely dissolved inthe solvent. The solvent swells the material of the elastic band andcarries the two agents into the elastic material of the band bydiffusion. The bands are soaked in the solution until equilibriumswelling of the band and diffusion of the agents into the material ofthe band has been achieved. The bands are then removed from the solutionand air-dried. Drying may also be accomplished in an oven. This causesthe volatile solvent to evaporate, trapping the agents within thematerial of the band. The evaporative drying process may also bring boththe anesthetic and the skin penetration enhancer to the surface of thedevice, where they remain as a coating on the band surface. This coatingprovides readily available anesthetic with skin penetration enhancer forwhen the band is first applied to an animal, while higher concentrationsof the agents residing in the material of the band and are released moreslowly over time as the band is worn by the animal, providing long termanesthetic activity.

Example 1

A solid elastration band made of latex rubber is soaked for 24 hours ina solution containing 25% by weight lidocaine free base, 25% by weightisopropyl myristate (IPM), a skin penetration enhancer, and 50% byweight of the volatile organic solvent tetrahydrofuran (THF). The bandis then removed from the solution, air-dried for 3-4 hours and dried inan oven at 170° F. for 30-60 minutes before it is packaged for use.

Example 2

A latex rubber elastration band is soaked as described in Example 1except that the solution contains 30% by weight lidocaine free base, 20%isopropyl myristate and 50% THF.

Example 3

A latex rubber elastic band is soaked as described in Example 1 or 2except that the solution also contains one or more skin permeationenhancers in a combined amount from 1-50% of the solution. Skinpermeation enhancers used by the invention may include (but are notlimited to) terpineol, limonene, esters derived from palm kemel oil,dimethyl sulfoxide (DMSO) and n-methyl pyrrolidone.

Example 4

A latex rubber elastic band is soaked as described in Examples 1-3except that the solution also contains from 1 to 10% of a water-solubleexcipient or surfactant to facilitate migration of the lidocaine to thesurface of the band. Examples of these additives include, but are notlimited to, glycerol, propylene glycol, polyethylene glycol,polypropylene glycol, nonoxynol 9 and other surfactants.

Example 5

A latex rubber elastic band is soaked as described in Examples 1-4except that the solution also contains a second anesthetic or analgesicagent in an amount from 1-20% of the solution. Secondary anesthetic oranalgesic agents useful for the invention include, but are not limitedto, lidocaine HCL or other salt, bupivacaine, levobupivacaine andmeloxicam. Other agents that enhance or prolong the action of theprimary anesthetic may also be incorporated into the solution. One suchagent that prolongs the activity of bupivacaine is epinephrine.

Example 6

A latex rubber elastration band is soaked as described in Example 1except that the solution contains 20% by weight of the slow releasinglidocaine free base, 10% by weight of the water soluble and fastreleasing lidocaine hydrochloride, 20% by weight isopropyl myristate(IPM), a skin penetration enhancer, and 50% by weight of the volatileorganic solvent tetrahydrofuran (THF).

Example 7

A latex rubber elastic band is soaked as described in any of theexamples above except that the solution also contains a second activeagent in an amount from 1-20% of the solution. Examples of these activeagents are an antimicrobial agent, an antibiotic, an anti-inflammatoryagent, a vasoconstrictor or a hormone.

Example 8

A latex rubber elastic band is soaked as described in any of theexamples above except that the solution also contains a dye, pigment,stain or pH indicator to act as a chemical indicator of agent release inan amount from 0.1-5% of the solution. In a preferred example, thechemical indicator is gentian violet, and it also acts as anantimicrobial agent.

Example 9

Silicone or other synthetic rubber elastic bands are soaked as describedin any of Examples 1 through 8.

Example 10

A thermoplastic polymer is compounded with one or more active agents asdescribed in the examples, and the compounded material is used toinjection mold the bands of the invention.

Example 11

A thermoplastic polymer is compounded with one or more active agents asdescribed in the examples, and the compounded material is used toextrude tubing that is cut into sections that become the elastrationbands of the invention.

Example 12

One or more of the active agents described in the examples arecompounded into silicone resin prepolymers, and then cast into molds orextruded into tubing and cured at elevated temperatures to fabricate theelastration bands of the invention.

Method 2: Injected Solution

Elastration bands are often made from hollow rubber tubing. For thesebands a different method may be used to infuse anesthetics and skinpenetration enhancers. Any of the solutions, anesthetics, skinpenetration enhancers and other agents described in Method 1 may also beused in Method 2. Rather than soaking the elastration band in asolution, the band may be treated by filling the tubing with thesolution and allowing time for it to swell the tubing and infuse itsrubber material with the agents. This can be accomplished in bulk with along piece of tubing before it is cut into sections that are formed intocircular bands, or the solution can be injected into the hollow centerof the tubing after the elastration band has been formed by fixing thetwo ends of a tubing section together. This method may also be combinedwith Method 1 by filling tubing previously coated as described in any ofExamples 1 through 12. The tubing may also be filled with aqueousemulsions of active agent(s) and skin penetration enhancers. Suchemulsions may be used in combination with the devices from Method 1 toprovide an additional reservoir of active agent for prolonged release.

Example 13

A length of hollow tubing is filled with any of the solutions fromexamples 1 through 8, and the tubing is allowed to dry in air or in anoven until all of the organic solvent has evaporated. Evaporation may befacilitated with heat and vacuum, as, for example, in a vacuum oven.Once the tubing has dried, a section of it is cut and the ends of thissection are fastened together to make an elastic loop that may be usedas an elastration band.

Example 14

The ends of a section of hollow tubing are fastened together to make aloop that may be used as an elastration band. Any of the solutionsdescribed in examples 1 through 8 are then injected by a syringe intothe hollow center of the band. The band is then dried to remove thevolatile organic solvent. Drying may be accomplished as described inExample 13. The band may be rotated during drying to provide a more evendistribution of the anesthetic agent in the band during drying.

Example 15

An aqueous emulsion of active agent(s), skin penetration enhancers and,optionally, solvent, is used in place of any of the solutions fromexamples 1 through 8 to fill the hollow center of the tubing in Examples8 and 9. The bands may or may not be dried, depending on whether asolvent that needs to be removed is used in the emulsion formula.

Method 3: Molding Formulations

Elastration bands containing an active agent composition may also befabricated by compounding active agents into thermoplastic materialsusing heat and shear, followed by fabrication of the elastration bandsby common methods of thermoforming.

Example 16

Active agents as described in any of Examples 1-8 are compounded intoany one of a number of elastomeric polymers or thermoplastic elastomersusing heat and shear by common methods such as, for example, twin-screwcompounding. The resulting compounded material is then used to injectionmold elastration bands, or the compounded material is extruded intotubing that is then cut into small sections and used as elastrationbands.

Example 17

Active agents as described in any of Examples 1-8 are compounded intoliquid silicone rubber (LSR) and used in reaction injection molding orextrusion to form elastration bands or tubing, respectively. Theextruded tubing is cut into sections that are used as elastration bands.

Example 18

Active agents as described in any of examples 1-8 are compounded into athermoset rubber or elastomer formulation, and molded or extruded tomake elastration bands by reaction injection molding (RIM).

Example 19

Any of the compounded formulations of Examples 16-18 may also becoextruded over other materials to make ligation devices of theinvention. In one preferred example, the compounded material is extrudedover wire to produce twist ties that contain active agents and can beused for ligation. In another example, the compounded material isextruded over a polypropylene core to produce zip-ties that can be usedfor ligation.

Method 4: Casting Formulations

Elastration bands containing an active agent composition may also befabricated from castable rubber or other castable elastomers. For thismethod the agents are mixed with the liquid prepolymer formulationbefore it is mixed with an activator that produces polymerization andcrosslinking to cure the formulation into a solid. After adding theactivator, the formulation is then cast into a mold to form a ring orband that can be used as an elastration device. Once the formulation hasbeen cast into a mold it is cured, typically by heating in an oven, toproduce the finished elastic band containing the anesthetic and skinpermeation enhancer.

Example 20

A castable, two-part RTV silicone rubber is used, and the anestheticagents, skin permeation enhancers and other ingredients are compoundedinto one or both parts of the formulation by mixing, before the twoparts are mixed together to begin the curing process. After mixing thetwo parts, the formulation is then cast into a mold where the RTVsilicone cures into an elastic silicone rubber containing the activeagents. Curing of the rubber may be accelerated by heating in an oven.Any of the agents described in examples 1 to 8 may be used.

Example 21: Formulation Development

Formulations containing 25% lidocaine (w/w) were prepared with fourdifferent skin penetration enhancers (SPE), (terpineol (TP), DMSO, IPM,and N-methyl pyrrolidone (NMP) being used at 33% of total solvent in THF(i.e. 33:67 SPE:THF). Four-inch sections of a latex catheter wereaffixed in a “U” to a metal wire and coated by soaking the U-section ineach formulation. They were then removed from solution and allowed toair dry for 48 hrs to evaporate all THF. Based on the observations ofcoating quality and the length of coating on the tube, it was determinedthat the formulation containing IPM produced the best coating, withterpineol a close second. DMSO produce about half the coating length ofIPM and TP, while NMP was the worst coating solvent and produced verylittle surface coating.

Example 22: Soak Coating

Initially, bands were swollen in coating formulations overnight toensure equilibrium swelling and maximum uptake of lidocaine. Whenswelling of the bands was studied as a function of time in the coatingformulation, it was found that 3 hours of swelling at room temperatureproduced near-equilibrium swelling that was sufficient to incorporatelidocaine into the band.

Example 23

Secondary Coating and Drying with Heat: Because THF evaporates rapidly,coated bands could be dried in air for a few hours, then the remainderof THF could be removed more quickly by drying in an oven with low heat.The final drying method combined air drying with oven drying to removeall of the THF while retaining most of the IPM in the band. Afterexperimenting with different lengths of air drying time from 1 to 3hours combined with 15 to 60 minutes oven drying at 170° F., it wasfound that 2 hours of drying in air followed by 30 minutes of ovendrying eliminated the THF from the coating while maintaining a highpercentage of the IPM. This is the drying method presently being usedfor the small green elastration bands. Bands of higher mass will requirelonger drying times.

Example 24

Extractables From Rubber: It is known that strong solvents like THF thatswell rubber will extract some low molecular weight unreacted componentsof the rubber. These extractables concentrate in a coating formulationas the number of elastration bands that is soaked in the formulationincreases. When the extractable concentration becomes too high in theformulation, it must be discarded and replaced with a fresh coatingsolution. This adds cost to the coating for each device. The addition ofa small amount of a non-solvent for rubber such as water or alcohol canreduce the amount of extractables in a THF coating formulation overtime.

In an effort to reduce rubber extractables, water was added to thelidocaine:IPM:THF formulation in amounts from 1 to 5% (w/w) based on thetotal solvent in the composition. Lower percentages of water (1-3%) werefound to be well tolerated by the formulation, but at higher percentages(4-5% water) lidocaine tended to precipitate from solution. To reducelidocaine precipitation, a combination of 5% ethanol, which is anonsolvent for rubber but a good solvent for lidocaine, and 1% water wasused in place of an equal amount of THF in the current formulation, andthis produced a formulation that did not precipitate lidocaine. Theeffect of these non-solvents on the % extractable from rubber has yet tobe evaluated, but it is anticipated that the inclusion of ethanol andwater will reduce extractables in the manufacture of coated elastrationbands, allowing longer use of coating solutions.

Example 25: Preferred Method for Making Lidocaine-Loaded Small GreenElastration Bands

Fifty green elastration bands were soaked for three hours in coatingsolution composed of 25.9% lidocaine, 22.8% IPM, 48.2% THF, 2.6%ethanol, and 0.50% H2O, and then hung to air dry in a hood for 3 hours.The rings were then dried in an oven at 170° F. for 30 minutes. Aftercooling, the rings were sealed in foil pouches.

Example 26

Lidocaine loading: Sample bands made to study the effect of non-solventson the coating formulation were evaluated for total concentration oflidocaine contained within the bands. Concentration of lidocainecontained within the bands was determined by high performance liquidchromatography (HPLC, United States Pharmacopoeia USP 29-NF24 Page1253). Test bands were placed in an appropriate vial with 15 mL of THFand a magnetic stir bar. These bands were extracted for 4 hours, then2.5 mL of the extraction sample was added to 50 mL of mobile phase (75%buffer and 25% acetonitrile). Lidocaine concentration was determined bycomparing unknown sample data to a five-point standard calibrationcurve. Lidocaine loading results based upon the results of HPLC analysisare presented in Table 1, and showed that lidocaine loading decreaseswith the addition of nonsolvent to the formulation.

TABLE 1 HPLC results demonstrating lidocaine loading in the ring as afunction of solvents utilized. Solvents Lidocaine % Lidocaine % THF %IPM % Ethanol % H2O (mg/ring) 25 66.6 33.4 79.1 25 66.6 33.4 6.7 69.2 2566.6 33.4 6.6 1.4 55.8As determined by HPLC, good loading of lidocaine into ligation bands ispossible utilizing various methods as described herein.

Example 27: Use of Ligation Band to Provide Lidocaine that AlleviatesPain During Castration

Small (4.3 cm) green elastrator bands with a lidocaine made in Example25 were tested in calves less than 200 pounds. This study investigatedthe efficacy of the prototype lidocaine elastration bands by assayingthe lidocaine levels remaining in used devices and in skin biopsies atthe site versus time of use on the animal. Indicators of pain in theanimal were used to assess the duration a therapeutic lidocaine levelwas maintained. Welfare observation techniques were also tested thatincluded physiology (temperature of affected site, weight) and behavior(continuous electronic (motion and pedometers to measure tail flicks)).24 animals were assigned to the test group (A: animals treated with alidocaine containing elastration band) and 24 animals were assigned tothe negative control group (B: lidocaine 20 mg/mL injection at the site,with an untreated elastration band). Rings were removed and tissuesamples taken at various time points post ligation application (0.5, 1,2, 4, 6, 24, 48, and 168 hours).

Average Daily Gain:

Average Daily Gain (ADG) was calculated for Day 7 calves. The differencefrom the pre-castration weight collected on day 0 was divided by 7, thenumber of days since day 0 (Table 2). The average on day 0 for theentire group (treatment and control) was 53.4 kg and on day 7 theaverage was 59.1 kg. Band type A group (Lidocaine band) had an ADG of0.886±0.647 kg/day and Band type B (plain band) had an ADG 0.729±0.272kg/day.

TABLE 2 average daily gain post castration by treatment group (Control Bvs Test A). Weight Day 0 Weight Day 7 ADG Test Animal (Kg) (Kg) (kg/day)Group 41 54.8 60.9 0.871 B 43 53.5 59.8 0.900 B 45 49.7 52.6 0.414 B 4051.8 62.8 1.571 A 42 49.3 51.3 0.286 A 44 61.5 67.1 0.800 A Summary ADG(kg/day) ±SD Control (B) 0.729 0.27 Test (A) 0.886 0.65

The slight increase in ADG in the test group indicates that thelidocaine eluting band did not have any negative impacts on animalbehavior and may indicate pain mitigation associated with the lidocainerelease by improved ADG (Marti et al, 2017).

Increased Tail-Flicking:

Increased Tail-flicking is an indicator of discomfort (Moya et al,2014), so pedometers attached to animal tails were used on all animalsto determine tail movements. Pedometer values were collected andrecorded at three time points, 0.5 hours, 6 and 48 hours after treatment(See Table 3). The Tail Flick data was organized into the treatmentgroups (A: Lidocaine Elastration Band and B: Injection lidocaine withplain band) at the different time points. There were three animalsassigned to each treatment group and time point. The average differencebetween the treatment groups was 15,885 for the 0.5 hr time point,15,718 for the 6 hour time point and 56,940 for the 48 hour time point.This data suggests pain mitigation associated with the lidocaine releaseby reduced tail flicks, which was especially significant at the 48 hrstime point, where the injected lidocaine of the Control would no longerbe providing anesthesia (Moya et al, 2014).

TABLE 3 Pedometer values over time (post elastration placement) fromtail attachment as an indicator of discomfort through tail movement. (A:Lidocaine Elastration Band prototype, B: injection lidocaine with plainband) Sample Number of tail Difference (Cotnrol - Group* Group swingsTest) 0.5 hours Control (B) 26,437 15,885 Test (A) 10,552   6 hoursControl (B) 18,513 15,718 Test (A) 2,795  48 hours Control (B) 89,55956,940 Test (A) 32,619 *Time in hours the pedometer was stopped, anddata recorded.

Tissue Temperature at Site: Temperature measurements over time were alsomade in the animal study of Example 27 to provide evidence of reducedinflammation and blood flow. Inflammation and blood flow are indicatorsof pain and healing at a wound site (Melendez et al, 2017). Images ofthe scrotal area, specifically the neck, were captured below and abovethe placement of the elastration bands applied in Example 27 using athermal imaging camera (FLIR E75-42). The temperatures registered andrecorded by the thermal camera of the target scrotal areas, above andbelow the elastration band, were recorded over the course of the study(FIG. 4 ). The temperature in Celsius, is plotted for the test andcontrol animals over time. For the first 48 hours there was nodifference in the two groups. The average temperature above the band forthe Control subjects was 36.39° C. and for the Test group was 36.36° C.Below the elastration band the average was 31.27° C. for the Control and31.85° C. for the Test. At the longer time point of 144 hours (day 7),the average temperatures were higher for the control group, with thebelow the band temperature at 32.47° C. for the Control, compared to30.03° C. for the Test Group. The decreased temperature below theligature band over time indicates proper ligature function and supportsthe claim of the invention functioning in this capacity. The reducedtemperature of the lidocaine containing ligature band compared to thecontrol band indicates reduced inflammation, which should correlate withreduced pain in the animal.

FIG. 4 shows temperature above and below the elastration band asmeasured at various intervals (hours) after application to the scrotum.Control (injected lidocaine with unmedicated band) and Test (lidocaineelastration band) subjects' data are plotted as squares and diamonds forthe control treatment and ‘x’ and‘+’ for the test treatment. Trend linesfor each data set are also depicted. This data demonstrates twoimportant elements: A) the reduction in blood flow (as measured bytemperature decrease) is greater in the test group over time compared tothe control indicating improved performance, and B) the reducedtemperature over time indicates that the bands function properly toreduce blood flow and cause castration by constriction.

Analysis of Lidocaine in Tissue: Tissue lidocaine levels obtained fromtissue biopsy samples taken directly underneath the elastration bandsover time (post elastration placement) as determined by HPLC analysisdemonstrates that the test bands (group A) deliver effectiveconcentrations of lidocaine (Yoshida et al, 2016) to the tissue over the48 hour sampling period versus the control, which only deliveredeffective lidocaine levels at the 6 hour time point. The levels oflidocaine associated with the tissue in the test group is significantlyhigher than in the control group at 24 and 48 hours, and is detected atlevels capable of producing a therapeutic effect.

TABLE 4 Tissue lidocaine levels obtained from tissue biopsy samplestaken directly underneath the elastration bands over time (postelastration placement, as determined by high performance liquidchromatography (HPLC) analysis), as an indicator of lidocaine deliveryto tissue. (A: Lidocaine Elastration Band prototype, B: Control,injection lidocaine with plain band). SD = standard deviation, samplingn = 3 per treatment group. ND = not detected (below the 0.0005 mg/g HPLCdetection limit), NA = Not Applicable MEAN (mg/g) ±SD  6 hr samplingCONTROL (B) 0.5610 0.19 TEST (A) 0.2500 0.32 24 hour sampling CONTROL(B) ND NA TEST (A) 0.0919 0.04 48 hour sampling CONTROL (B) 0.0069 NA*TEST (A) 1.0286 1.16 *only 1 sample of three had detection of lidocaineabove the 0.0005 mg detection limitTissue Collection and Processing Methodology:

Rings were removed and tissue samples (4 mm biopsy punches) taken atvarious time points post ligation application (6, 24, and 48 hours) inthe animal study of Example 27. Biopsy samples were dissolved in 2 mL 1M NaOH at 37° C. for 3 hours. The sample was then neutralized by theaddition of HCl. A liquid-liquid extraction procedure is conducted asfollows: 0.01 mL of a 120 mg/mL solution in 95% ethanol of an internalstandard (tetracaine) is added to the homogenized tissue sample, and thesample is vortexed for 15 seconds. 5 mL of ethyl ether is then added,and the sample is vortexed again for 15 seconds. The ether layer isallowed to separate for 2 minutes, then it is removed and evaporated todryness. The residue is then dissolved in 1 mL of HPLC grade methylalcohol, and HPLC analysis is conducted. Effective tissue concentrationsin the tissue are typically between 0.150 and 0.500 mg/g tissue.Reference: Tanaka, E, Yoshida K, Kawaai H., Yamazaki S. 2016. “Lidocaineconcentration in oral tissue by the addition of epinephrine”. Anesth Prg63:17-24.

VII. Definitions

The following definitions are used in reference to the invention: (A) Asused herein, pre-determined length is a length suitable for the size ofthe body part being ligated, and is within the know-how of those skilledin the art. Typically, the elastomeric band must be of such structureand elastic nature that when stretched about the neck of the scrotalpouch of an animal and there fastened, it has sufficient elasticconstriction force to cause ligation. It must also allow sufficientexpansion for passage of the scrotal pouch and contained testicularstructure of a large mature animal such as a bovine bull through theorifice defined by the stretched band without breakage. For fastenedtubular elastrators, the band must also provide sufficient material toallow fastening in a tensed condition by a deformable metallic fasteningclip or similar fastening structure. Normally such a band formed ofnatural rubber will require a cross-sectional area of approximately 0.1to 0.4 square inch when the cross-sectional configuration is of arectangular form. Such a band normally will have a relaxed diameter offrom approximately one half to three inches. These parameters may varygenerally with the nature of the elastomeric material and particularlyfor specific purposes while such bands remain operative for castration,and such variant bands are within the ambition and scope of theinvention.

VIII. References

-   Crank, John. “Diffusion in a cylinder.” Chap. 5 in The Mathematics    of Diffusion. London: Oxford university Press, 1975.    http://www-eng.lbl.gov/˜shuman/NEXT/MATERIALS%26COMPONENTS/Xe_damage/Crank-The-Mathematics-of-Diffusion.pdf    (Accessed Mar. 16, 2018).-   United States Pharmacopoeia USP 29-NF24 Page 1253-   Marti S, Meléndez D M, Pajor E A, Moya D, Heuston C E M, Gellatly D,    Janzen E D, Schwartzkopf-Genswein K S. Effect of band and knife    castration of beef calves on welfare indicators of pain at three    relevant industry ages: II. Chronic pain. J Anim Sci. 2017 October;    95(10):4367-4380.-   Moya D, Gonzalez L A, Janzen E, Caulkett N A, Fireheller E,    Schwartzkopf-Genswein K S. Effects of castration method and    frequency of intramuscular injections of ketoprofen on behavioral    and physiological indicators of pain in beef cattle. J Anim Sci.    2014 April; 92(4):1686-97.-   Meléndez D M, Marti S, Pajor E A, Moya D, Heuston C E M, Gellatly D,    Janzen E D, Schwartzkopf-Genswein K S. Effect of band and knife    castration of beef calves on welfare indicators of pain at three    relevant industry ages: I. Acute pain. J Anim Sci. 2017 October;    95(10):4352-4366.-   Tanaka, E, Yoshida K, Kawaai H., Yamazaki S. 2016. “Lidocaine    concentration in oral tissue by the addition of epinephrine”. Anesth    Prg 63:17-24.

We claim:
 1. A method of making a ligation band configured for topicalcontrol of pain during use, the method comprising: providing a ligationband formed from an elastomeric material; preparing a solutioncomprising a solvent selected to swell the elastomeric material, one ormore anesthetics, and one of a skin permeation enhancer or a skinpenetration enhancer; submersing the ligation band in the solution tothereby infuse the ligation band with the solution; removing theligation band from solution; and drying the ligation band to remove thesolvent therefrom, whereby the one or more anesthetics, and one of askin permeation enhancer or a skin penetration enhancer are distributedwithin and throughout the ligation band.
 2. The method of claim 1,wherein the elastomeric material is one of a natural rubber, a syntheticrubber, a silicone, a polybutadiene, a polyisoprene, a polychloroprene,a nitrile, a poly(styrene-butadiene-styrene) (SBS), astyrene-ethylene-butylene-styrene (SEBS), an ethylene-propylene-dienemonomer rubber (EPDM), a polyurethane, and combinations thereof.
 3. Themethod of claim 1, wherein: the anesthetic is selected from a groupconsisting of lidocaine, bupivacaine, proparacaine HCl, benzocaine,mepivacaine, bupivacaine liposomal, ropivacaine, chloroprocainehydrochloride, levobupivacaine, and combinations there of; and the skinpermeation enhancer is selected from a group consisting of isopropylmyristate, fatty acids, fatty acid esters, poloxamers, triglycerides,n-methyl pyrrolidone, terpineol, limonene, dimethyl sulfoxide,dimethylacetamide, and combinations thereof.
 4. The method of claim 1,wherein the solution additionally comprises one or more antimicrobialagents, one or more antibiotics, or combinations thereof.
 5. The methodof claim 1, wherein the solution additionally comprises: one or moreanti-inflammatory compounds selected from a group consisting offlunixin, ketoprofen, diclofenac, ibuprofen, meloxicam, dexamethasone,flumethasone, prednisolone, and prednisone; and/or one or more hormonesselected from a group consisting of cortisone, hydrocortisone,trenbolone, testosterone, and estradiol; and/or one or more chemicalindicators selected from a group consisting of Nile Red, Oil Red, SudanRed, Congo Red, cresol red, Coomassie Red, Coomassie Blue, methyleneblue, Oil Blue, gentian violet, Azure blue, Malachite green, Eosin dyes,Rhodamine dyes, haematoxylin, phenolphthalein, resazurin, phenol red,methyl red, bromothymol blue, thymol blue, Alizarin yellow, povidoneiodine, indigo, turmeric, Catechu and Annatto extract; and/or one ormore vasoconstrictors selected from a group consisting of epinephrine,pseudoephedrine, phenylephrine, thromboxane, and angiotensin.